Durban, KwaZulu Natal, South Africa is the epicenter of the global HIV pandemic, where a large number of people infected with HIV are also co-infected with TB. The MRC Clinical Trials Unit (MRC CTU) is internationally renowned for conducting large scale trials of HIV prevention including microbicides, vaginal diaphragm, and oral Pre-Exposure Prophylaxis (PrEP); HIV therapeutic trials, and socio-behavioral studies. Six well-established clinical research sites (CRSs) are located in the greater Durban area, where HIV incidence among young women ranges from 5.1/100PY (in earlier research) to 16.4/100PY (in 2012). Lack of effectiveness in earlier trials was due to multiple factors, including poor adherence. The current understanding of the epidemic suggests a need for an integrated approach to HIV and TB prevention, treatment, and linkage to care. The MRC CTU's primary goal is to integrate site operations, community partnerships, and responses to adherence challenges/behavioral research by partnering with 4 Networks to meet the following aims: AIM 1: Conduct HIV prevention trials of long-acting microbicides and oral PrEP and HIV vaccines in at-risk populations. We hypothesize that long-acting formulations in this population may circumvent adherence challenges. AIM 2: Conduct therapeutic trials of novel, safe, effective, and robust regimens. We hypothesize that cost-effective, third-line treatment regimens will be needed in the foreseeable future in our setting. AIM 3: To undertake RCTs of HIV-associated co-morbidities. There are critical gaps in TB treatment that we propose to address by developing and participating in trials using molecular diagnostics to determine treatment duration and optimize drug regimens for multidrug-resistant TB. AIM 4: Integrated strategies to address the epidemic. No single HIV prevention option will address the epidemic. We hope to participate in trials testing integrated strategies of HIV prevention, as well as those integrating prevention and treatment of both HIV and TB, with effective linkage to care. The MRC CTU has access to the population at-risk, a well-developed and centralized CRS infrastructure, and the experience and expertise of international consultants to undertake and deliver on the proposed research aims. RELEVANCE: This comprehensive attempt to address the dual HIV/TB pandemic in Durban, South Africa through an integrated approach of testing novel HIV prevention strategies, novel HIV therapeutics agents for future options, and addressing HIV co-morbidity with TB with appropriate linkage to care, will provide the empirical data to guide future real-world development and implementation of effective HIV and TB strategies.